Emileigh Johnson

Comparative Efficacy of Inactivated and Live Attenuated Influenza Vaccines

BACKGROUND The efficacy of influenza vaccines may vary from year to year, depending on a variety of factors, and may differ for inactivated and live attenuated vaccines. METHODS We carried out a randomized, double-blind, placebo-controlled trial of licensed inactivated and live attenuated influenza vaccines in healthy adults during the 2007-2008 influenza season and estimated the absolute and relative efficacies of the two vaccines. RESULTS A total of 1952 subjects were enrolled and received study vaccines in the fall of 2007. Influenza activity occurred from January through April 2008, with the circulation of influenza types A (H3N2) (about 90%) and B (about 9%). Absolute efficacy against both types of influenza, as measured by isolating the virus in culture, identifying it on real-time polymerase-chain-reaction assay, or both, was 68% (95% confidence interval [CI], 46 to 81) for the inactivated vaccine and 36% (95% CI, 0 to 59) for the live attenuated vaccine. In terms of relative efficacy, there was a 50% (95% CI, 20 to 69) reduction in laboratory-confirmed influenza among subjects who received inactivated vaccine as compared with those given live attenuated vaccine. The absolute efficacy against the influenza A virus was 72% (95% CI, 49 to 84) for the inactivated vaccine and 29% (95% CI, -14 to 55) for the live attenuated vaccine, with a relative efficacy of 60% (95% CI, 33 to 77) for the inactivated vaccine. CONCLUSIONS In the 2007-2008 season, the inactivated vaccine was efficacious in preventing laboratory-confirmed symptomatic influenza A (predominately H3N2) in healthy adults. The live attenuated vaccine also prevented influenza illnesses but was less efficacious. (ClinicalTrials.gov number, NCT00538512.)

Efficacy Studies of Influenza Vaccines: Effect of End Points Used and Characteristics of Vaccine Failures

BACKGROUND End points used to detect influenza in vaccine efficacy trials have varied. Both the inactivated and live attenuated influenza vaccines are efficacious; however, failure to protect occurs. METHODS We compared characteristics of influenza A (H3N2) and B cases from 3 years of a comparative placebo-controlled trial of inactivated and live attenuated vaccines, and we evaluated the laboratory end points used to determine efficacy. RESULTS Although illness duration and reported symptoms did not differ by intervention, subjects with influenza in the inactivated vaccine group were less likely than those in the placebo group to report medically attended illnesses. All influenza type A (H3N2) and B cases isolated in cell culture were also identified by real-time polymerase chain reaction (rtPCR). However, only 69% of type A (H3N2) cases identified by rtPCR also were isolated in cell culture. Isolation frequency was lowest among live attenuated vaccine failures, a reflection of lower specimen viral loads. Among cases of rtPCR identified influenza A (H3N2), 90% of placebo and 87% of live attenuated vaccine recipients but only 23% of inactivated vaccine recipients demonstrated serologic confirmation of infection. CONCLUSIONS In influenza vaccine efficacy studies, virus identification using rtPCR is the ideal end point. Isolation in cell culture will miss cases, and a serologic end point alone will overestimate inactivated vaccine efficacy.

Antibody to Influenza Virus Neuraminidase: An Independent Correlate of Protection

BACKGROUND Laboratory correlates of influenza vaccine protection can best be identified by examining people who are infected despite vaccination. While the importance of antibody to viral hemagglutinin (HA) has long been recognized, the level of protection contributed independently by antibody to viral neuraminidase (NA) has not been determined. METHODS Sera from a controlled trial of the efficacies of inactivated influenza vaccine (IIV) and live attenuated influenza vaccine (LAIV) were tested by hemagglutination inhibition (HAI) assay, microneutralization (MN) assay, and a newly standardized lectin-based neuraminidase inhibition (NAI) assay. RESULTS The NAI assay detected a vaccine response in 37% of IIV recipients, compared with 77% and 67% of participants in whom responses were detected by the HAI and MN assays, respectively. For LAIV recipients, the NAI, HAI, and MN assays detected responses in 6%, 21%, and 17%, respectively. In IIV recipients, as NAI assay titers rose, the frequency of infection fell, similar to patterns seen with HAI and MN assays. HAI and MN assay titers were highly correlated, but NAI assay titers exhibited less of a correlation. Analyses suggested an independent role for NAI antibody in protection, which was similar in the IIV, LAIV, and placebo groups. CONCLUSIONS While NAI antibody is not produced to a large extent in response to current IIV, it appears to have an independent role in protection. As new influenza vaccines are developed, NA content should be considered. CLINICAL TRIALS REGISTRATION NCT00538512.

Influenza transmission in a cohort of households with children: 2010-2011.

Background Households play a major role in community spread of influenza and are potential targets for mitigation strategies. Methods We enrolled and followed 328 households with children during the 2010-2011 influenza season; this season was characterized by circulation of influenza A (H3N2), A (H1N1)pdm09 and type B viruses. Specimens were collected from subjects with acute respiratory illnesses and tested for influenza in real-time reverse transcriptase polymerase chain reaction (RT-PCR) assays. Influenza cases were classified as community-acquired or household-acquired, and transmission parameters estimated. Results Influenza was introduced to 78 (24%) households and transmission to exposed household members was documented in 23 households. Transmission was more likely in younger households (mean age <22 years) and those not reporting home humidification, but was not associated with household vaccination coverage. The secondary infection risk (overall 9.7%) was highest among young children (<9 years) and varied substantially by influenza type/subtype with the highest risk for influenza A (H3N2). The serial interval (overall 3.2 days) also varied by influenza type and was longest for influenza B. Duration of symptomatic illness was shorter in children compared with adults, and did not differ by influenza vaccination status. Discussion Prospective study of households with children over a single influenza season identified differences in household transmission by influenza type/subtype, subject age, and home humidification, suggesting possible targets for interventions to reduce transmission.

Substantial Influenza Vaccine Effectiveness in Households With Children During the 2013–2014 Influenza Season, When 2009 Pandemic Influenza A(H1N1) Virus Predominated

BACKGROUND We examined the influenza vaccine effectiveness (VE) during the 2013-2014 influenza season, in which 2009 pandemic influenza A(H1N1) virus (influenza A[H1N1]pdm09) predominated. In 2 previous years when influenza A(H3N2) virus predominated, the VE was low and negatively affected by prior year vaccination. METHODS We enrolled and followed 232 households with 1049 members, including 618 children; specimens were collected from subjects with acute respiratory illnesses. The VE in preventing laboratory-confirmed influenza A(H1N1)pdm09 infection was estimated in adjusted models. Preseason hemagglutination-inhibition and neuraminidase-inhibition antibody titers were determined to assess susceptibility. RESULTS Influenza A(H1N1)pdm09 was identified in 25 households (10.8%) and 47 individuals (4.5%). Adjusted VE against infection with influenza A(H1N1)pdm09 was 66% (95% confidence interval [CI], 23%-85%), with similar point estimates in children and adults, and against both community-acquired and household-acquired infections. VE did not appear to be different for live-attenuated and inactivated vaccines among children aged 2-8 years, although numbers were small. VE was similar for subjects vaccinated in both current and prior seasons and for those vaccinated in the current season only; susceptibility titers were consistent with this observation. CONCLUSIONS Findings, including substantial significant VE and a lack of a negative effect of repeated vaccination on VE, were in contrast to those seen in prior seasons in which influenza A(H3N2) virus predominated.

Persistence of Antibodies to Influenza Hemagglutinin and Neuraminidase Following One or Two Years of Influenza Vaccination

BACKGROUND Antibody titers to influenza hemagglutinin (HA) and neuraminidase (NA) surface antigens increase in the weeks after infection or vaccination, and decrease over time thereafter. However, the rate of decline has been debated. METHODS Healthy adults participating in a randomized placebo-controlled trial of inactivated (IIV) and live-attenuated (LAIV) influenza vaccines provided blood specimens immediately prior to vaccination and at 1, 6, 12, and 18 months postvaccination. Approximately half had also been vaccinated in the prior year. Rates of hemagglutination inhibition (HAI) and neuraminidase inhibition (NAI) titer decline in the absence of infection were estimated. RESULTS HAI and NAI titers decreased slowly over 18 months; overall, a 2-fold decrease in antibody titer was estimated to take >600 days for all HA and NA targets. Rates of decline were fastest among IIV recipients, explained in part by faster declines with higher peak postvaccination titer. IIV and LAIV recipients vaccinated 2 consecutive years exhibited significantly lower HAI titers following vaccination in the second year, but rates of persistence were similar. CONCLUSIONS Antibody titers to influenza HA and NA antigens may persist over multiple seasons; however, antigenic drift of circulating viruses may still necessitate annual vaccination. Vaccine seroresponse may be impaired with repeated vaccination.

Vaccination has minimal impact on the intrahost diversity of H3N2 influenza viruses

While influenza virus diversity and antigenic drift have been well characterized on a global scale, the factors that influence the virus’ rapid evolution within and between human hosts are less clear. Given the modest effectiveness of seasonal vaccination, vaccine-induced antibody responses could serve as a potent selective pressure for novel influenza variants at the individual or community level. We used next generation sequencing of patient-derived viruses from a randomized, placebo-controlled trial of vaccine efficacy to characterize the diversity of influenza A virus and to define the impact of vaccine-induced immunity on within-host populations. Importantly, this study design allowed us to isolate the impact of vaccination while still studying natural infection. We used pre-season hemagglutination inhibition and neuraminidase inhibition titers to quantify vaccine-induced immunity directly and to assess its impact on intrahost populations. We identified 166 cases of H3N2 influenza over 3 seasons and 5119 person-years. We obtained whole genome sequence data for 119 samples and used a stringent and empirically validated analysis pipeline to identify intrahost single nucleotide variants at ≥1% frequency. Phylogenetic analysis of consensus hemagglutinin and neuraminidase sequences showed no stratification by pre-season HAI and NAI titer, respectively. In our study population, we found that the vast majority of intrahost single nucleotide variants were rare and that very few were found in more than one individual. Most samples had fewer than 15 single nucleotide variants across the entire genome, and the level of diversity did not significantly vary with day of sampling, vaccination status, or pre-season antibody titer. Contrary to what has been suggested in experimental systems, our data indicate that seasonal influenza vaccination has little impact on intrahost diversity in natural infection and that vaccine-induced immunity may be only a minor contributor to antigenic drift at local scales.

Modest Waning of Influenza Vaccine Efficacy and Antibody Titers during the 2007-2008 Influenza Season

BACKGROUND Antibody titers decrease with time following influenza vaccination, raising concerns that vaccine efficacy might wane. However, the relationship between time since vaccination and protection is unclear. METHODS Time-varying vaccine efficacy (VE[t]) was examined in healthy adult participants (age range, 18-49 years) in a placebo-controlled trial of inactivated influenza vaccine (IIV) and live-attenuated influenza vaccine (LAIV) performed during the 2007-2008 influenza season. Symptomatic respiratory illnesses were laboratory-confirmed as influenza. VE(t) was estimated by fitting a smooth function based on residuals from Cox proportional hazards models. Subjects had blood samples collected immediately prior to vaccination, 30 days after vaccination, and at the end of the influenza season for testing by hemagglutination inhibition and neuraminidase inhibition assays. RESULTS Overall efficacy was 70% (95% confidence interval [CI], 50%-82%) for IIV and 38% (95% CI, 5%-59%) for LAIV. Statistically significant waning was detected for IIV (P = .03) but not LAIV (P = .37); however, IIV remained significantly efficacious until data became sparse at the end of the season. Similarly, antibody titers against influenza virus hemagglutinin and neuraminidase significantly decreased over the season among IIV recipients. CONCLUSIONS Both vaccines were efficacious but LAIV less so. IIV efficacy decreased slowly over time, but the vaccine remained significantly efficacious for the majority of the season.

The Household Influenza Vaccine Effectiveness Study: Lack of Antibody Response and Protection Following Receipt of 2014–2015 Influenza Vaccine

Background Antigenically drifted A(H3N2) viruses circulated extensively during the 2014-2015 influenza season. Vaccine effectiveness (VE) was low and not significant among outpatients but in a hospitalized population was 43%. At least one study paradoxically observed increased A(H3N2) infection among those vaccinated 3 consecutive years. Methods We followed a cohort of 1341 individuals from 340 households. VE against laboratory-confirmed influenza was estimated. Hemagglutination-inhibition and neuraminidase-inhibition antibody titers were determined in subjects ≥13 years. Results Influenza A(H3N2) was identified in 166 (12%) individuals and B(Yamagata) in 34 (2%). VE against A(H3N2) was -3% (95% confidence interval [CI]: -55%, 32%) and similarly ineffective between age groups; increased risk of infection was not observed among those vaccinated in 2 or 3 previous years. VE against influenza B(Yamagata) was 57% (95% CI: -3%, 82%) but only significantly protective in children <9 years (87% [95% CI: 43%, 97%]). Less than 20% of older children and adults had ≥4-fold antibody titer rise against influenza A(H3N2) and B antigens following vaccination; responses were surprisingly similar for antigens included in the vaccine and those similar to circulating viruses. Antibody against A/Hong Kong/4801/14, similar to circulating 2014-2015 A(H3N2) viruses and included in the 2016-2017 vaccine, did not significantly predict protection. Conclusions Absence of VE against A(H3N2) was consistent with circulation of antigenically drifted viruses; however, generally limited antibody response following vaccination is concerning even in the context of antigenic mismatch. Although 2014-2015 vaccines were not effective in preventing A(H3N2) infection, no increased susceptibility was detected among the repeatedly vaccinated.

Factors associated with real-time RT-PCR cycle threshold values among medically attended influenza episodes.

We evaluated the cycle threshold (CT) values of 1,160 influenza A positive and 806 influenza B positive specimens from two seasons of the US Flu VE Network to identify factors associated with CT values. Low CT values (high genomic load) were associated with shorter intervals between illness onset and specimen collection, young age (ages 3–8 years old), and self‐rated illness severity for both influenza A and B. Low CT values were also associated with reported fever/feverishness and age ≥65 years for influenza A. J. Med. Virol. 88:719–723, 2016.